About FBXO31
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FBXO31 c.1000G>A, p.(Asp334Asn)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
In a published functional study, fibroblast assays from affected individuals showed reduced cyclin D abundance compared with controls, and the authors interpreted p.Asp334Asn as causing increased cyclin D degradation. This result supports a damaging functional effect for the variant.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Its observed population frequency is therefore 0, which is below the 0.1% threshold used here to support rarity.
PM6Moderate
PM6 · moderate
This variant has been reported as de novo in three unrelated affected individuals across two publications. Because formal maternity and paternity confirmation was not documented in the retrieved evidence, these observations support PM6 rather than PS2.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM2 supporting, PM6 moderate; combination = 1 strong + 1 moderate + 1 supporting, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 10 not met · 7 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The FBXO31 c.1000G>A (p.Asp334Asn) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with pathogenic and likely pathogenic clinical submissions.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0 and is below the 0.1% threshold used here to support rarity.
In a published functional study, fibroblast assays from affected individuals showed reduced cyclin D abundance relative to controls, and the authors interpreted p.Asp334Asn as causing increased cyclin D degradation, supporting a damaging effect on FBXO31 function.
Published reports describe recurrent de novo occurrence in three unrelated affected individuals, while computational evidence is mixed: SpliceAI predicts no splice effect with a max delta score of 0.00, REVEL is 0.455, and BayesDel is -0.150532, so in silico data alone do not strongly support either PP3 or BP4.
No criteria match.
Met · 3
PS3 StrongIn a published functional study, fibroblast assays from affected individuals showed reduced cyclin D abundance compared with controls, and the authors interpreted p.Asp334Asn as causing increased cyclin D degradation. This result supports a damaging functional effect for the variant. Details ▾Hide ▴
Evidence considered
- Patient fibroblast cyclin D abundance assay
- Variant-specific functional interpretation consistent with damaging effect
Sources
PMID:32989326 ↗32989326
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Its observed population frequency is therefore 0, which is below the 0.1% threshold used here to support rarity. Details ▾Hide ▴
PM6 ModerateThis variant has been reported as de novo in three unrelated affected individuals across two publications. Because formal maternity and paternity confirmation was not documented in the retrieved evidence, these observations support PM6 rather than PS2. Details ▾Hide ▴
Evidence considered
- Two de novo affected individuals reported in 2020
- One additional de novo affected individual reported in 2021
Still missing
- Formal maternity and paternity confirmation was not documented in the retrieved evidence.
Sources
Not met · 10 · evaluated, threshold not reached
PS2 This variant has been reported as de novo in affected individuals, but the retrieved evidence did not document formal maternity and paternity confirmation. The de novo observations therefore do not meet the full requirements for PS2. Details ▾Hide ▴
Evidence considered
- Two de novo affected individuals reported in 2020
- One additional de novo affected individual reported in 2021
Still missing
- Formal maternity and paternity confirmation was not documented in the retrieved evidence.
Sources
PS4 This variant has been reported in multiple affected individuals, but no formal case-control enrichment analysis or other quantitative evidence was identified to show that its prevalence is significantly increased in affected individuals compared with controls. Details ▾Hide ▴
Evidence considered
- Three reported affected individuals
- Variant absent from gnomAD
Still missing
- No case-control or odds-ratio style analysis was identified for this exact variant.
Sources
PM1 Asp334 lies in a cyclin D interaction region of FBXO31, but available evidence does not show that this residue or region is a well-established mutational hotspot or a critical domain without benign variation. Cancer Hotspots also did not identify a statistically significant hotspot at this position. Details ▾Hide ▴
Evidence considered
- Asp334 is in the cyclin D interaction site
- No statistically significant hotspot found
Still missing
- No curated missense hotspot or benign-variation-depleted region was identified for residue 334.
Sources
PP1 No segregation data were identified showing that this variant cosegregates with disease in affected relatives. Details ▾Hide ▴
Evidence considered
- Published cases described de novo occurrence rather than familial segregation
Still missing
- No family segregation data were identified.
Sources
PP3 Computational evidence is mixed and does not strongly support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.455, and BayesDel is -0.150532; these values do not provide strong pathogenic computational support. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.455
- BayesDel -0.150532
Sources
BA1 This variant is absent from gnomAD v2.1 and v4.1, so its population frequency is well below the 1% threshold for BA1. Details ▾Hide ▴
BS1 This variant is absent from gnomAD v2.1 and v4.1, so its population frequency is below the 0.3% threshold used here for BS1 and does not support a benign interpretation. Details ▾Hide ▴
BS3 No published functional study was identified showing normal or benign FBXO31 function for this variant. Available functional evidence instead supports a damaging effect. Details ▾Hide ▴
Evidence considered
- Published functional study supports abnormal effect rather than normal function
Still missing
- No normal-function assay result was identified for this variant.
Sources
PMID:32989326 ↗32989326
BS4 No evidence was identified showing lack of segregation with disease or unaffected carriers in informative families. Details ▾Hide ▴
Evidence considered
- Published cases were de novo rather than discordant segregation cases
Still missing
- No nonsegregation evidence was identified.
Sources
BP4 Computational evidence does not consistently support a benign effect. Although SpliceAI predicts no splice impact with a max delta score of 0.00 and BayesDel is -0.150532, REVEL is 0.455, so the overall in silico evidence is not strong enough for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.455
- BayesDel -0.150532
Sources
Not assessed · 7 · no assessment recorded
PS1 No evidence was identified showing that a different nucleotide change producing the same amino acid substitution has already been established as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar exact-variant review
Still missing
- No same-amino-acid pathogenic comparison variant was identified.
Sources
PM5 No evidence was identified showing that a different missense change at codon 334 has already been established as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar exact-variant review
Still missing
- No alternate pathogenic missense change at the same codon was identified.
Sources
PP2 Available evidence was not sufficient to determine whether FBXO31 is a gene in which pathogenic missense variation is a common disease mechanism and benign missense variation is uncommon. Details ▾Hide ▴
Evidence considered
- Exact-variant and literature review
Still missing
- A curated gene-level missense constraint and pathogenic-variant spectrum assessment was not available.
Sources
PP4 Published affected individuals had a recurrent neurodevelopmental phenotype with prominent motor dysfunction, but the phenotype specificity for applying PP4 to this individual case was not established from the available evidence. Details ▾Hide ▴
Evidence considered
- Reported affected individuals with spastic-dystonic cerebral palsy spectrum features
Still missing
- Case-specific phenotype data for the individual under review were not available.
Sources
BS2 No evidence was identified showing this variant in healthy adult individuals for a disorder with expected full penetrance at an early age. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
Still missing
- No unaffected carrier data were identified.
Sources
BP2 No evidence was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with another pathogenic variant. Details ▾Hide ▴
Evidence considered
- No phase information identified
Still missing
- No phase data with another pathogenic variant were identified.
Sources
BP5 No alternate molecular cause was identified that would explain the reported disease phenotype independently of this variant. Details ▾Hide ▴
Evidence considered
- Published case report context
Still missing
- No comprehensive alternate-cause assessment was available for the individual under review.
Sources
PMID:33675180 ↗33675180
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the generic PVS1 framework is not applicable because the variant does not create a nonsense, frameshift, or canonical ±1,2 splice change. Although gene-level review indicated that loss of function may be a disease mechanism for FBXO31, this specific variant does not meet the null-variant entry criteria for PVS1. Details ▾Hide ▴
Evidence considered
- FBXO31 loss-of-function mechanism was considered at the gene level
- c.1000G>A is a missense change outside the generic PVS1 null-variant categories
Sources
PM3 N/ANo evidence was identified for this variant in trans with a pathogenic variant in a recessive disease context, so PM3 is not applicable. Details ▾Hide ▴
PM4 N/AThis is not an in-frame deletion, in-frame insertion, or protein length change, so PM4 is not applicable. Details ▾Hide ▴
PP5 N/APP5 was not applied because assertion by an external source without independently reviewable evidence is not used here. Details ▾Hide ▴
BP1 N/ABP1 was not applied because available evidence does not show that FBXO31 disease is caused primarily by truncating variants with missense variants generally benign. Details ▾Hide ▴
Evidence considered
- Recurrent disease-associated missense variant reported in affected individuals
Sources
BP3 N/AThis is not an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴
BP6 N/ABP6 was not applied because assertion by an external source without independently reviewable evidence is not used here. Details ▾Hide ▴
BP7 N/AThis criterion is not applicable because the variant is missense rather than synonymous or deep intronic. Details ▾Hide ▴
Identifiers
- Gene
- FBXO31
- Transcript
- NM_024735.5
- Coding (HGVS c.)
- NM_024735.5:c.1000G>A
- Protein (HGVS p.)
- NP_079011.3:p.(Asp334Asn)
- GRCh38
- chr16:87334283 C>T
- GRCh37
- chr16:87367889 C>T
Gene diagram
Every interpreted variant in FBXO31, mapped onto the exon structure of NM_024735.5. Select a row to find it on the plot.
FBXO31NM_024735.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in FBXO31
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Computational evidence is mixed and does not strongly support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.455, and BayesDel is -0.150532; these values do not provide strong pathogenic computational support. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.455
- BayesDel -0.150532
Sources
BP4 Computational evidence does not consistently support a benign effect. Although SpliceAI predicts no splice impact with a max delta score of 0.00 and BayesDel is -0.150532, REVEL is 0.455, so the overall in silico evidence is not strong enough for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.455
- BayesDel -0.150532
Sources
BP7 N/AThis criterion is not applicable because the variant is missense rather than synonymous or deep intronic. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.455. BayesDel score = -0.150532.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1344806/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-87367889-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-87334283-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024735.5%3Ac.1000…
- OncoKB ↗www.oncokb.org/gene/FBXO31/D334N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FBXO31+c.1000G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.455. BayesDel score = -0.150532.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.